Lilly's Drug Flop Shows How Tough Alzheimer's Will Be To Beat

Long gone are the golden years of the 1990s when Big Pharma rolled out one hit drug after another. New pills to treat conditions that affected many millions of people -- such as high cholesterol, depression and impotence -- became huge sellers.

But as Eli Lilly just found out the hard way, the challenge of finding medicines to treat intractable illnesses like Alzheimer's disease is in a whole other league.

The drugmaker said yesterday it was pulling the plug on an experimental medicine called semagacestat after it bombed in late-stage clinical tests. Those studies are supposed to provide the proof needed by the Food and Drug Administration for approval, and even these days a failure at that stage is unusual for a big drugmaker.

The problem for semagacestat wasn't just that it didn't work. The medicine, which block an enzyme involved in the formation of so-called amyloid plaques in the brain, made Alzheimer's patients worse.

That "completely unexpected result," as Lilly researcher Dr. Eric Siemers put it to the New York Times, spelled the end for semagacestat and also delivered a blow to the amyloid hypothesis as an explanation for how Alzheimer's disease.

Duke psychiatrist P. Murali Doraiswamy, co-author of the Alzheimer's Action Plan, told the Wall Street Journal's Health Blog, "There’s very good evidence that the plaques play a strong role in familial Alzheimer’s, and in animal models they are toxic." But, as he explained, doctors and scientists don't understand the interaction between plaques and tangles, another hallmark, and the long "timeline of events" that lead to Alzheimer's.

As Forbes' Robert Langreth notes the Lilly results may bolster the arguments of researchers who've long been skeptical of the amyloid hypothesis, saying the plaques are a bystander to dementia -- not its cause. Is amyloid dead as a drug target? "It is impossible to tell based on the limited amount of data Lilly has provided," Langreth writes.

But, at the least, the setback for Lilly raises fresh questions about the best route for attacking Alzheimer's.

Update: In the worst light, the Lilly results may spell doom for drug that try to fight Alzheimer's by blocking the enzyme gamma secretase. As Derek Lowe, a drug company scientist and blogger, writes:

This is about as bad a result as could possibly be obtained, and I think it really has to torpedo the idea of gamma secretase as a drug target. Unless someone comes up with a very compelling and intricate argument to explain these results, I don't see how anyone can risk going down this particular road again.

Right now, he adds, is the moment of truth for the amyloid hypothesis, "with several different approaches finally yielding late-stage clinical data," he explains. "And it's starting to look as if the whole idea may have been just a terrible diversion."